Molecular Defects of Insulin Signaling in PCOS

PCOS 中胰岛素信号传导的分子缺陷

• 批准号: 6719108
• 负责人: Ricardo Azziz
• 金额: $ 7.65万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6719108
• 关键词: SDS polyacrylamide gel electrophoresis; adipocytes; biological signal transduction; clinical research; female; glucose transporter; human subject; immunoprecipitation; insulin; insulin receptor; mitogen activated protein kinase; molecular pathology; phosphorylation; polycystic ovary syndrome; protein kinase; western blottings; women' s health

DESCRIPTION (provided by applicant): The polycystic ovary syndrome (PCOS) affects about 4% of reproductive-aged women, and is one of the most common causes of oligo-ovulatory infertility. Between 50% and 70% of women with PCOS demonstrate insulin resistance, independent of body weight, and the resulting compensatory hyperinsulinemia leads to the hyperandrogenic features of the disorder. Overall, little is know about the molecular aspects of the insulin signaling defects of PCOS. Previous studies have indicated that insulin-stimulated glucose transport is deficient, suggesting an alteration along the PI-3 kinase/Akt/GLUT-4 cascade. Alternatively, mitogenic activity in response to insulin appears to be normal in the fibroblasts of these patients, suggesting that the MAPK pathway may be unaffected in PCOS. Based on these observations we have hypothesized that abnormal insulin receptor (IR) signaling in adipose tissues is a frequent abnormality in women with PCOS; and that the defect is present downstream from the IR, affecting the PI-3 kinase/Akt/GLUT-4, but not the MAPK, pathway. We have also hypothesized that the insulin resistance of PCOS may be more closely related to abnormalities of visceral (omental) than subcutaneous fat. Our Specific Aim is to determine whether abnormal IR signaling is present in the adipocytes of patients with PCOS. Specifically, we will test our hypothesis by studying the abdominal subcutaneous and omental adipose tissues of 10 normal-weight or pre-obese PCOS patients and 10 age/race/body massmatched controls. In these tissues we will determine: i) the total amount and the degree of phosphorylation in response to insulin of the IR, the IR substrate-1 and 2 proteins (IRS-1/2), and of critical intermediate proteins (i.e., Akt, GSK-3, and FKHR of the PI-3 kinase/Akt cascade; c-Raf, MEK-1, ERKI/2, and p90RSK of the ERKI/2 cascade; JNK of the SAPK/JNK cascade; and p38 MAPK of the cascade of the same name) and the translational regulator p70 S6; and ii) the total amounts of GLUT-4 and IRS-associated PI-3 kinase. We should note that this systematic approach to investigating insulin signaling is critical at this early stage in the study of the mechanisms underlying insulin resistance in PCOS. Long term, these studies have the potential of eventually elucidating the etiologic mechanism(s) in some, or most, patients; helping to develop targeted therapies; and guiding the search for molecular markers for PCOS.

描述（由申请人提供）：多囊卵巢综合征 (PCOS) 影响约 4% 的育龄女性，是少排卵不孕的最常见原因之一。 50% 至 70% 的 PCOS 女性表现出胰岛素抵抗，与体重无关，由此产生的代偿性高胰岛素血症导致该疾病的高雄激素特征。总体而言，人们对多囊卵巢综合征胰岛素信号传导缺陷的分子方面知之甚少。先前的研究表明，胰岛素刺激的葡萄糖转运存在缺陷，表明 PI-3 激酶/Akt/GLUT-4 级联发生了改变。另外，这些患者的成纤维细胞对胰岛素的促有丝分裂活性似乎正常，这表明 MAPK 通路在 PCOS 中可能不受影响。基于这些观察，我们假设脂肪组织中胰岛素受体 (IR) 信号异常是 PCOS 女性常见的异常现象。该缺陷存在于 IR 下游，影响 PI-3 激酶/Akt/GLUT-4，但不影响 MAPK 通路。 我们还假设PCOS的胰岛素抵抗可能与内脏（网膜）异常的关系比皮下脂肪的关系更密切。 我们的具体目标是确定 PCOS 患者的脂肪细胞中是否存在异常 IR 信号。具体来说，我们将通过研究 10 名正常体重或肥胖前期 PCOS 患者和 10 名年龄/种族/体重匹配对照者的腹部皮下和网膜脂肪组织来检验我们的假设。在这些组织中，我们将确定： i) IR、IR 底物 1 和 2 蛋白 (IRS-1/2) 以及关键中间蛋白（即 PI-3 激酶/Akt 级联的 Akt、GSK-3 和 FKHR； ERKI/2级联； SAPK/JNK 级联的 JNK；和同名级联的 p38 MAPK）和翻译调节因子 p70 S6； ii) GLUT-4 和 IRS 相关 PI-3 激酶的总量。 我们应该注意到，这种研究胰岛素信号传导的系统方法在研究多囊卵巢综合征胰岛素抵抗机制的早期阶段至关重要。从长远来看，这些研究有可能最终阐明一些或大多数患者的病因机制；帮助开发靶向疗法；并指导寻找多囊卵巢综合症的分子标记。